13,13A-Didehydroberbine derivatives

ABSTRACT

The present invention provides a cholesterol biosynthesis inhibitor which specifically inhibits the sterol 14-reductase which is involved in the distal pathway of cholesterol biosynthesis, a compound of formula (1) below and the use of an extract or the compound of formula (1) for treating hypercholesterolaemia or hyperlipidaemia. The inhibitor comprises an extract obtained by extracting Corydalis Turtschaninowii Besser with a solvent, or an organic layers obtained by partitioning an extract from Corydalis Turtschaninowii Besser with an organic solvent. The extract contains 7,8,13,13α-tetrahydrocoridaline or its derivative, as the active ingredients, which specifically inhibits the enzyme which is involved in the distal pathway of the cholesterol biosynthesis.                    
     R 1  and R 2  which may be the same or different from each other, represent a hydroxy group or an alkoxy group having 1 to 4 carbon atoms or both of R 1  and R 2  represent a methylenedioxy group; 
     R 3  represents a hydrogen atom; 
     R 4  and R 5  which may be the same or different from each other, represent a hydroxy group, a hydroxyethylamino group or an alkoxy group having 1 to 4 carbon atoms; 
     R 6  represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 8 carbon atoms, a cycloalkylalkyl group having 1 to 7 carbon atoms, a holoalkyl group having 1 to 4 carbon atoms, an ethoxycarbonyl group, an ethoxycarbonylmethyl group, a hydroxycarbonylmethyl group, 1-ethoxycarbonylethyl group, or 2-valerolactonyl group.

TECHNICAL FIELD

The present invention relates to a cholesterol biosynthesis inhibitor.More specifically, the present invention relates to a new class ofinhibitor which specifically inhibits the sterol 14-reductase which isinvolved in the distal pathway of cholesterol biosynthesis. Theinhibitor comprises an extract obtained by extracting CorydalisTurtschaninowii Besser with a solvent, or an organic layer obtained bypartitioning an extract from Corydalis Turtschaninowii Besser with anorganic solvent. The extract contains 7,8,13,13αa-tetrahydroridaline orits derivatives, as a main ingredient. The present invention alsorelates to a novel compound of formula (1) as set forth below and to theuse of the extract or the compound of formula (1) for treatinghypercholesterolemia or hyperlipidaemia.

BACKGROUND ART

Cholesterol is an important vital constituent of cell membrane in mammaland is involved in cell division, growth, development and control ofdifferentiation, and also is a precursor of various essentialmetabolites (for example, steroid hormones, bile acids). However, it maycause hyperlipidaemia which leads to atherosclerosis if its intake orproduction within the body is excess. Hyperlipidaemia leads tocardiovascular disease which is a leading cause of death in humans. Itis usually caused when cholesterol or triglyceride has exceeded a properlevel (i.e., total cholesterol level for adults at the age of between 30and 40 is about 200 mg/dl), and then, deposited to the inner wall of anartery to form atheroma plaques, thereby blood flow being inhibitedwhich causes cardiac failure or cerebral stroke. Cholesterol issynthesized mainly in the liver in mammals and the synthetic pathwaythereof is started from acetyl-CoA and is completed after at least 32steps of enzyme reactions.

Cholesterol biosynthesis which occurs in mammal can be summarizedaccording to the enzyme reaction patterns in which each intermediate isformed as in the following reaction scheme 1.

In the above reaction scheme, steps I and II undergo polymerization, andsteps II and III undergo cyclization. In step IV, transformation,demethylation, isomerization or reduction of steroid ring is proceeded.Cholesterol biosynthesis is carefully controlled by the multi-stepregulation, i.e., the so-called multivalent coordinate regulation. Forexample, 3-β-hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase) isthe main rate-limiting enzyme in the cholesterol biosynthesis. Itreduces HMG-CoA synthesized from acetyl-CoA during the early stage ofthe biosynthetic pathway starting from acetate (C2) to mevalonate (C6)and is inhibited in vivo by the final product, cholesterol. Morespecifically, the activity of this enzyme is controlled by dietarycholesterol, oxysteroids and mevalonate derivatives in a feed-backinhibition manner. For the past decade, the lipid-lowering agents havebeen developed based on their inhibiting activities against this enzyme.Most of currently marketed therapeutic agents for hyperlipidaemia whichhave been developed based on such mechanism include, for example,statins including lovastatin, pravastatin, simvastatin, atorvastatin,and cerivastatin. However, if cholesterol biosynthesis is suppressed byinhibiting the activity of HMG-CoA reductase which is the rate limitingenzyme at the early stage of cholesterol biosynthesis, there may be manyside effects that the synthesis of many important biomolecules such asdolicol, isopentenyl pyrophosphate, haem A, and ubiquinone which arealso derived from mevalonate are suppressed together.

Therefore, it may be advantageous to block cholesterol biosynthesis at astep distal to HMG CoA reductase in order to prevent depletion of suchessential intermediates.

Accordingly, recent researches have been focused on the development ofnew type of therapeutic agents for hyperlipidaemia which can effectivelyblock only the post-squalene steps without interfering HMG-CoA reductaseactivity. For example, the activation mechanisms of the distal enzymesresponsible for the postsqualene pathway in the cholesterol biosynthesiswhich comprises the sequence of‘squalene→lanosterol→zymosterol→desmosterol→cholesterol’ have beenstudied and attempts to screen and develop a drug which can specificallyinhibit the activity of the target enzyme responsible for the distalpathway of cholesterol biosynthesis based have been made. Especially,based on the inhibitory activity of squalene epoxidase responsible forthe pathway of ‘squalene—>lanosterol’, a benzylamine series compound,NB598 has been developed by Banyu Pharmaceutical Co. of Japan;Squalenestatin I has been developed by the researchers of Glaxo WellcomeLimited, a British company on the basis of its inhibition of squalenesynthase which is responsible for the synthesis of squalene fromfarnesyl pyrophosphate.

RPR107393 has been developed as a potent squalene synthase inhibitor byresearchers at Rhone-Poulenc, France. Further, Taton et al. havereported MDL 28,815 having 8-azadecaline ring based on the inhibition of2,3-oxidosqualene cyclase responsible for the cyclization reaction inwhich squalene epoxide is converted into methylsterol (See, Biochem.Biophys. Res. Commun. 1986, 138, 764-70). These NB598, Squalenestatin I,RPR107393 and MDL 28,815 which inhibit the activities of enzymesresponsible for the post-mevalonate pathway in the cholesterolbiosynthetic pathway have a merit that they can selectively inhibit thecholesterol biosynthesis without effecting on the production of otherimportant intermediates which are derived from mevalonate, differentlyfrom drugs that have a target on HMG-CoA reductase responsible for theearly stage of cholesterol biosynthesis.

However, these agents are not yet currently marketed as therapeuticagents for hyperlipidaemia.

DISCLOSURE OF THE INVENTION

The present inventors have conducted a extensive research for many yearsin order to develop a novel class of cholesterol biosynthetic inhibitorwhich specifically inhibits the enzyme involved in the steps of‘lanosterol—>cholesterol’. As a result, the inventors have surprisinglydiscovered that an extract obtained from Corydalis TurtschaninowiiBesser which has been used in the prescription of sedative agent orhemostatic agent in the oriental medicine for thousand years stronglyinhibits the activity of sterol 14-reductase which catalyzes thereduction of 4,4-dimethyl-8,14-dien-3β-ol and thus have completed thepresent invention.

Based on these findings, it is possible to provide a cholesterolbiosynthesis inhibitor which comprises an extract obtained fromCorydalis Turtschaninowii Besser containing7,8,13,13α-tetrahydrocoridaline as the main component which specificallyinhibits the sterol 14-reductase in the distal pathway of thecholesterol biosynthesis.

It is therefore an object of the present invention to provide acholesterol biosynthesis inhibitor which comprises an extract obtainedby extracting Corydalis Turtschaninowii Besser with one or more solventselected from the group consisting of water, alcohols, such as methanol,ethanol, and dichloromethane and/or an organic fraction obtained bypartitioning an extract from Corydalis Turtschaninowii Besser with anorganic solvent such as dichloromethane.

Another object of the present invention is to provide a cholesterolbiosynthesis inhibitor which comprises the components isolated from theorganic fraction of the above Corydalis Turtschaninowii Besser extractor synthetic derivatives of the components.

A further object of the present invention is to provideprotoberberine(5,6-dihydrodibenzo-[a,g]quinolizinium) derivatives or13,13α-didehydroberbine derivatives or the salts thereof which can berepresented by formula (1) as set forth below.

Still another object of the present invention is to provide acomposition for inhibiting cholesterol biosynthesis, especiallyinhibiting sterol 14-reductase, which comprises7,8,13,13α-tetrahydrocoridaline, or protoberberine(5,6-dihydrodibenzo-[a,g]quinolizinium) derivatives,13,13α-didehydroberbine derivatives or the salts thereof which can berepresented by formula (1) below and a pharmaceutically acceptablecarrier.

A still further object of the present invention is to provide apharmaceutical composition for treating hypercholesterolemia orhyperlipidaemia which comprises pharmaceutically effective amount of theabove extract, the organic fraction or the synthetic derivatives as anactive ingredient and a pharmaceutically acceptable carrier.

Still another object of the present invention is to provide a method fortreating hypercholesterolemia and hyperlipidaemia by inhibitingcholesterol biosynthesis, especially inhibiting sterol 14-reductase withthe above pharmaceutical composition.

Further objects and advantages of the invention will become apparentthrough reading the remainder of the specification.

The foregoing has outlined some of the more pertinent objects of thepresent invention. These objects should be construed to be merelyillustrative of some of the more pertinent features and applications ofthe invention. Many other beneficial results can be obtained by applyingthe disclosed invention in a different manner or modifying the inventionwithin the scope of the disclosure. Accordingly, other objects and amore thorough understanding of the invention may be had by referring tothe detailed description of the preferred embodiment in addition to thescope of the invention defmed by the claims.

Hereinbelow, the application will be illustrated in more detail.

The extract from Corydalis Turtschaninowii Besser according to thepresent invention can be prepared by triturating CorydalisTurtschaninowii Besser into small pieces, extracting them with a 80%ethanol in warm bath, filtering the extract, and evaporating theextracted solution under reduced pressure to remove the solvent. As thesolvent for the extraction, water, alcohols such as methanol or ethanol,dichloromethane or the mixture thereof may be preferably used.

Corydalis Turtschaninowii Besser is an annual plant widely distributedin the mountains and fields of Korea and has been used in theprescription of sedative agent or hemostatic agent in the orientalmedicine. An extract of Corydalis Turtschaninowii Besser contains a lotof alkaloids as a major active component, of which is coridaline in theform of quaternary ammonium salt. This coridaline in the form ofquaternary ammonium salt has been known to have a week sedative actionand a strong gastric juice secretion action, and UK Patent No. 1,265,627and German Patent No. 2,043,218 disclose its use as an anti-ulcer agent.

However, the use of an extract obtained from Corydalis TurtschaninowiiBesser comprising 7,8,13,13α-tetrahydrocoridaline, an alkaloid, the maincomponent of which is coridaline as a cholesterol biosynthesis inhibitorhas not yet been reported. The inventors of the present invention havediscovered the use of Corydalis Turtschaninowii Besser as a cholesterolsynthesis inhibitor in the course of screening new cholesterolbiosynthesis inhibitor based on the oriental medicine. This discoverywas fully supported by the method using a screening an activity ofsterol 14-reductase that was established by the inventors since theinventors have started the research for a new drug.

The detailed screening method will be explained in detail in the workingexamples. Thus, the principle thereof will be briefly explainedhereinbelow.

That is, sterol 14-reductase is one of the main regulatory enzymes forlanosterol→cholesterol pathway and is responsible for the reduction ofthe double bond formed when methyl group attached to the carbon at14-position of lanosterol is demethylated. First, a screening system forsterol 14-reductase was constructed in which4,4-dimethyl-5α-cholesta-7,14-dien-3β-ol is used as a substrate andthen, the effect on the activity of sterol 14-reductase was investigatedin the screening system. It is possible to obtain the correlation that asubstance inhibiting the activity of sterol 14-reductase inhibitscholesterol biosynthesis by comparing the results obtained from thescreening tests with those of the actual animal experiments.

The synthetic derivative for the purpose of the present invention isprotoberberine (5,6-dihydro-dibenzo-[a,g]quinolizinium) or13,13α-didehydroberbine derivative which can be represented by theformula (1) below.

R¹ and R² which may be the same or different from each other, representa hydroxy group or an alkoxy group having 1 to 4 carbon atoms or both ofR¹ and R² represent a methylenedioxy group;

R³ represents a hydrogen atom;

R⁴ and R⁵ which may be the same or different from each other, representa hydroxy group, a hydroxyethylamino group or an alkoxy group having 1to 4 carbon atoms;

R⁶ represents a hydrogen atom, an alkyl group having 1 to 8 carbonatoms, an alkenyl group having 3 to 8 carbon atoms, a cycloalkylalkylgroup having 1 to 7 carbon atoms, a holoalkyl group having 1 to 4 carbonatoms, an ethoxycarbonyl group, an ethoxycarbonylmethyl group, ahydroxycarbonylmethyl group, 1-ethoxycarbonylethyl group, or2-valerolactonyl group; and

Z represents a halogen atom, or

wherein, if

R¹ and R² which may be the same or different from each other, representa hydroxy group or an alkoxy group having 1 to 4 carbon atoms or both ofR¹ and R² represent a methylenedioxy group;

R³ represents a hydrogen atom; an alkyl group having 1 to 8 carbonatoms, a ketonyl group having 3 to 7 carbon atoms, a cycloalkyl grouphaving 3 to 7 carbon atoms, a cyanomethyl group, 2-cyclopentanonylgroup, or 2-cyclohexanonyl group;

R⁴ and R⁵ which may be the same or different from each other, representa hydroxy group, ahydroxyethylamino group or an alkoxy group having 1 to4 carbon atoms;

R⁶ represents a hydrogen atom, an alkyl group having 1 to 8 carbonatoms, an alkenyl group having 3 to 8 carbon atoms, or a cycloalkylalkylgroup having 1 to 7 carbon atoms.

The cholesterol biosynthesis inhibitor according to the presentinvention, especiallyprotoberberine(5,6-dihydrodibenzo-[a,g]quinolizinium) derivative,13,13α-didehydroberbine derivative or the salts thereof as the inhibitorof sterol 14-reductase can preferably be represented by Tables 1 and 2below:

TABLE 1 protoberberine derivative formula (1a)

Compound No. R¹ R² R⁴ R⁵ R⁶ Z m.p.(° C.)  1 —O—CH₂—O— CH₃O CH₃O CH₃ I168  2 OH OH CH₃O CH₃O CH₃ Cl 145  3 OH OH OH OH H Cl 163  4 OH OH OH OHCH₃ Cl 255  5 EtO EtO EtO EtO Et Cl 128  6 —O—CH₂—O— CH₃O CH₃O Et I 230 7 OH OH OH OH Et Cl 280  8 CH₃O CH₃O CH₃O CH₃O Et Cl 186  9 —O—CH₂—O—CH₃O CH₃O Allyl I 165 10 OH OH OH OH Allyl Cl 234 11 CH₃O CH₃O CH₃O CH₃On-Pr I 190 12 CH₃O CH₃O CH₃O CH₃O n-Bu I 170 13 CH₃O CH₃O CH₃O CH₃O

I 230 14 CH₃O CH₃O CH₃O CH₃O n-Octyl I 128 15 CH₃O CH₃O CH₃O CH₃O

I 198 16 CH₃O CH₃O CH₃O CH₃O

I 156 17 n-BuO n-BuO n-BuO n-BuO H Cl 180 18 CH₃O CH₃O CH₃O CH₃O

Cl 146 19 CH₃O CH₃O CH₃O CH₃O

Cl  92 20 CH₃O CH₃O CH₃O CH₃O

Cl 200 21 CH₃O CH₃O CH₃O CH₃O

Cl 198 22 —O—CH₂—O— CH₃O CH₃O

Br 187 23 —O—CH₂—O— CH₃O CH₃O

Br 240 24 —O—CH₂—O— CH₃O CH₃O

Br 165 25 CH₃O CH₃O

CH₃O Et Cl 214

TABLE 2 13,13α-didehydroberbine derivative formula (1b)

Compound No. R¹ R² R⁴ R⁵ R³ R⁶ m.p.(° C.) 26 —O—CH₂—O— CH₃O CH₃O

H 130 27 —O—CH₂—O— CH₃O CH₃O CH₃ H  96 28 —O—CH₂—O— CH₃O CH₃O Et H  9029 —O—CH₂—O— CH₃O CH₃O n-Pr H  90 30 —O—CH₂—O— CH₃O CH₃O n-Bu H  68 31—O—CH₂—O— CH₃O CH₃O

H 107 32 —O—CH₂—O— CH₃O CH₃O i-Pr H  98 33 CH₃O CH₃O CH₃O CH₃O CH₃ H  7534 CH₃O CH₃O CH₃O CH₃O Et H  86 35 —O—CH₂—O— CH₃O CH₃O noctyl H liquid36 —O—CH₂—O— CH₃O CH₃O

H 162 37 CH₃O CH₃O CH₃O CH₃O

Et 156 38 CH₃O CH₃O CH₃O CH₃O

Et 127 39 CH₃O CH₃O CH₃O CH₃O

Et  72 40 CH₃O CH₃O CH₃O CH₃O

Et 127 41 CH₃O CH₃O CH₃O CH₃O

Et 147 42 CH₃O CH₃O CH₃O CH₃O

Et 165 43 CH₃O CH₃O CH₃O CH₃O

Et 125 44 EtO EtO EtO EtO

Et 45 EtO EtO EtO EtO

Et 103 46 CH₃O CH₃O CH₃O CH₃O H Et 122 47 EtO EtO EtO EtO H Et 103 48CH₃O CH₃O CH₃O CH₃O CH₃ Et 134 49 CH₃O CH₃O CH₃O CH₃O Et Et 153 50 CH₃OCH₃O CH₃O CH₃O n-Bu Et 112

A part of the compounds represented by the formula (1) according to thepresent invention may exist as the main component for CorydalisTurtschaninowii Besser alkaloid. However, since the amount thereofavailable from nature is limited, it may be synthesized starting fromthe compound of formula (4) below according to the reaction scheme 2below as described in UK Patent No. 1,265,627.

In the above reaction scheme 2, R³ and R⁶ are the same as defined in theabove compound of formula (1), and X represents a halide, a sulfate, ora nitrate.

In the first step of the reaction scheme, berberine salt of structuralformula (4) is reacted with a ketone compound under the presence of abase such as sodium hydroxide or diisopropyl amine and normal butyllithium to give 8-ketonylberberine compound represented by formula (5)or reacted with alkyl lithium or alkyl magnesium halide to give 8-alkylberberine compound represented by formula (5).

In the second step, 8-acetonylberberine and alkyl halide are reacted at50˜100° C. in a polar solvent such as acetonitrile or a non-polarsolvent such as toluene to give 13-alkylberberine halide of formula (6).

The third step of the above reaction scheme involves the cleavagereaction of 2,3-methylenedioxy ring in which the compound of formula (6)is reacted with Lewis acid such as anhydrous aluminum chloride at80˜160° C. and then subjected trihydrolysis reaction with a dilute acid.According to the reaction conditions, 13-alkyl-2,3-dihydroxy compoundmay be produced as a major product along with 2,3,9-trihydroxy-, or2,3,9,10-tetrahydroxy compound and these compounds can be separated byrecrystalization method. However, it may be possible to be used in thefourth step reaction without further separation process.

The fourth step involves a reaction in which the compound of formula (7)obtained from the previous step is methylated with a methylating reagentsuch as dimethyl sulfate or iodomethane to give 13-alkylpalmatine saltof formula (8). In this reaction step, the compound wherein alkyl at13-alkyl group is methyl is dehydrocoridaline compound (comp. no. 8 inTable 1).

13-alkylpalmatine salt represented by formula (8) may be transformedinto various salts such as halide, sulfate, nitrate, acetate, cinnamate,tinate, maleate, succinate, citrate, fumarate or fatty acid salt, etc.on the basis of the salts used in the purification process of the fourthstep. The carbonyl group of ketone in the 8-ketonylberberine of formula(5) can be reduced using lithium aluminum hydride. Quaternary ammoniumsalts represented by the formulae (4), (6), (7) and (8) may be reducedwith sodium borohydride (NaBH₄) in the presence of potassium carbonateto give tertiary amine compounds.

Meanwhile, among the protoberberine compound of formula (1 a), thecompound wherein R¹, R², R³, R⁴, R⁵ and R⁶ each represents a methoxygroup, a methoxy group, a hydrogen atom, a methoxy group, a methoxygroup and an ethyl group and Z represents chloride, and the compoundwherein R¹, R², R³, R⁴, R⁵ and R⁶ each represents an ethoxy group, anethoxy group, a hydrogen atom, an ethoxy group, an ethoxy group and anethyl group and Z represents chloride; and among the didehydroberbinecompound of formula (1 b), the compound wherein R¹, R², R³, R⁴, R⁵ andR⁶ each represents a methoxy group, a methoxy group, a 2-oxopropylgroup, a methoxy group, a methoxy group and an ethyl group, and thecompound wherein R¹, R², R³, R⁴, R⁵ and R⁶ each represents a methoxygroup, a methoxy group, a hydrogen atom, a methoxy group, a methoxygroup and an ethyl group and Z represents chloride are preferred in anaspect of the pharmaceutical efficacy.

The compound of formula (1) markedly inhibited the cholesterolbiosynthesis in the cultured human liver cell culture (HepG2 cell line).In order to investigate the effect of the compound of formula (1) of theinvention, the compound was orally administered into male Syrian GoldenHamsters having weights of 90˜110 g and then blood was taken from eachaninal. Plasma lipids, i.e., total cholesterol, LDL-cholesterol,HDL-cholesterol and triglycerides were analyzed using an automaticanalyzer (Automatic analyzer model Hitachi 7150). As the results, totalcholesterol, LDL-cholesterol, and triglyceride levels were significantlydecreased while HDL-cholesterol value was not significantly changed. Inaddition, the compound resulted in decrease in a certain degree in theglucose value within the serum.

The compound of formula (1) may be formulated into a pharmaceuticalcomposition with pharmaceutically acceptable excipients or carriers.Especially, the composition can be desirably used as the therapeuticagents for treating hypercholesterolemia and hyperlipidaemia byinhibiting sterol 14-reductase. The composition may be formulated into atablet, a syrup or an injection formulation and thus, can beadministered orally. An effective dose will vary depending upon the kindof the excipients or carriers within the range for treatinghypercholesterolemia and hyperlipidaemia with a dose of 0.3˜60 mg/kg/dayof active ingredient being preferable in case of oral administration.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in greater detail by way of thefollowing examples and synthetic examples. The examples are provided forthe purpose of illustration only and should not be construed as limitingthe invention which is properly delineated in the claims.

EXAMPLE 1 Inhibiting Effect of an Extract from Corydalis TurtschaninowiiBesser on Sterol 14-reductase in Microsome State

100 G of Corydalis Turtschaninowii Besser were homogenated and then,added into a 1 L flask equipped with a reflux condenser together with300 ml of 80% methanol. The mixture was extracted for 3 hours underreflux. The filtrates were combined and dried over a reduced pressureroller condenser at a temperature below 60° C. to give 9.2 g ofCorydalis Turtschaninowii Besser extract. Separately, 20 maleSprague-Dawley rats weighing from 150 to 200 g have been fed a dietcontaining 0.1% (w/w) Lovastatin and 5% (w/w) Cholestyramine. Theanimals were fasted for 12 hours before excising liver tissues and thensacrificed by decapitation at midnight. An aqueous solution containing0.25 M of sucrose was injected into the hepatic portal vein to removeall the blood within the liver, and then, the liver was excised. Theliver was homogenated with two volummes of buffer solution 1 (0.1 Mpotassium phosphate , 1 mM reduced glutathione, 0.5 mM EDTA, 20% (v/v)glycerol, pH 7.4) by repeating pestles over 10 times and then,centrifuged with 900×g for 5 minutes to give a supematant. Thesupernatant was centrifuged with 12,000×g for 20 minutes. The supematantobtained was ultracentrifuged with 105,000×g for 90 minutes to give amicrosome which was used as an enzyme source of sterol 14-reductase.Assay against sterol 14-reductase was carried out as follows: 60 nmol of4,4-dimethyl-5α-cholesta-7,14-dien-3β-ol and the extract from CorydalisTurtschaninowii Besser dissolved into DMSO were added to an assaymixture (total volume 1.0 ml) containing 2 mg of microsomal protein, 2mM of NADPH and 25 mg of glucose plus 20 units of glucose oxidase withpreincubations under nitrogen at 37° C. for 4 min unless otherwisespecified to establish anaerobic condition. Buffer A (0.1M potassiumphosphate buffer, pH 7.4, including 1 mM reduced glutathione, 0.5 mMEDTA, and 20% (v/v) glycerol) used for incubation had been equilibratedwith nitrogen, and nitrogen was exchanged for air in all sealed reactionflasks prior to the start of incubations. Incubation of the completemixture was carried out anaerobically in sealed flasks for 10 min at 37°C. unless otherwise indicated. Incubations were terminated by theaddition of 1 ml of ethanolic KOH followed by heating under reflux for10 min. Sterols were extracted four times with 4 ml of petroleum ether,and the solvent was evaporated to dryness under a nitrogen stream. Theresulting residue was dissolved in 200˜500 μl of n-hexane forquantification by GLC at high sensitive attenuation. The activity ofsterol 14-reductase was determined with the amount of the substratewherein the double bonds of 14-carbon were reduced (for the amountreduced by 1 mg of the microsome protein for 1 minute). When CorydalisTurtschaninowii Besser level added to the reaction system was 5 mg/ml,57% of inhibition of the enzymatic activity was observed.

EXAMPLE 2 Effect of Alkaloid Fractions from Corydalis TurtschaninowiiBesser on Sterol 14-reductase Activity

10.0 G of Corydalis Turtschaninowii Besser extracts were dissolved into200 ml of distilled water and the mixture was then transferred to aseparatory funnel. Solvent partition was carried out with 200 ml ofdichloromethane. After layers were separated, dichloromethane layerswere combined together and this extraction procedure was repeated twicewith 150 ml of dichloromethane. Combined organic extracts were driedover anhydrous magnesium sulfate, filtered and concentrated. Afterremoving solvent with a vacuum pump, 1.45 g of the organic fractions inpowder were obtained. The organic solvent fractions of CorydalisTurtschaninowii Besser extracts obtained by the above procedure weredissolved in DMSO and tested for the activity on sterol 14-reductase asthe same manner in Example 1. When the fraction level was 50 μg/ml, 37%of inhibitory effect was observed.

EXAMPLE 3 Effect of the Alkaloid Fractions from CorydalisTurtschaninowii Besser on Cholesterol Biosynthesis ratio in CHO Cells

Chinese hamster ovary cell (CHO cell) was passage-cultivated on the flatplates. When colonies reached at 70 to 80% of area based on the totalculture area, culture medium was replaced with a fresh medium and thiswas then used as samples for determining sterol 14-reductase activityand the cholesterol biosynthesis ratio.

Cholesterol biosynthesis ratio was determined by the Boogaard method[See, Biochem. J. 1987, 241, 345-51] with some modification. To thethree dishes (diameter: 60 nm) containing the above CHO cells, theextracts obtained from Example 2 were added and the mixture was thenincubated for 30 minutes. After adding each 0.5 μCi of ¹⁴C-Mevalonateinto the medium, incubation was continued for 2 hours. Culture mediumwas removed from the vessel, and the mixture was then washed 3 timeswith PBS at 4° C. The cells were scratched and collected in about 1.0 mlof PBS, and then subjected to centrifugation at 10,000 rpm for 5 min. Inorder to determine cholesterol having radioactivity, the cellprecipitates were first floated with 0.1 N NaOH. After quantifyingproteins in the floats, the floated material were taken so as to containa suitable amount of proteins. The total volume was adjusted to 1.0 mlwith the buffer solution 1 and added 1.0 ml of 25% ethanolic KOHsolution thereto to proceed saponification reaction at 80° C. for 30minutes. After dissolving unsaponicated sterols into n-hexane, they wereseparated by a thin layer liquid chromatography. The composition of thedeveloping solvents was ethyl acetate and benzene at 95:5 ratio andcholesterol was developed as the internal standard for 50 minutes. Bandsin the cholesterol-developed peak region were collected and put into aradioactive vial, and then 10 ml of scintillation cockail solution wereadded thereto. The radioactivity strength of each sample was determinedby a liquid scintillation counter (LSC) to give the cholesterolbiosynthetic ratio. 81% of inhibitory effect was observed at the 50μg/ml concentration of the organic fractions from the extract.

EXAMPLE 4 Effect of 7,8,13,13α-tetrahydrocoridaline Which is an ActiveIngredient of Corydalis Turtschaninowii Besser on Sterol 14-reductaseActivity

3.0 G of the organic fraction powder were adsorbed on celite and it wasthen placed on the upper end of the liquid chromatography for aliquot.Dichloromethane and ethanol were used as elution solvents. At the earlypathway of the chromatography, elution was carried out withdichloromethane only, and then, ethanol content was gradually increased.It was confirmed by the thin layer chromatography that most of7,8,13,13α-tetrahydrocoridaline with a small amount of impurity werefound in the fractions in which 4˜6% of ethanol/dichloromethane elutionsolvent were used. The fractions were combined, concentrated and thenrefluxed in distilled water for 10 minutes. Undissolved components werefiltered off and the filtrate was stored for 24 hours in a refrigerator.The crude crystals formed were dried and then recrystallized frommethanol to give 120 mg of 7,8,13,13α-tetrahydrocoridaline. Thestructure of 7,8,13,13α-tetrahydrocoridaline was identified with thenuclear magnetic resonance spectrometer, mass analyzer, and infraredspectrometer. The result are set forth below.

¹H-NMR (CD₃OD, 300 MHz), δ: 3.00(s, 3H), 3.21(t, 2H), 3.95(s, 3H),4.01(s,

3H), 4.11(s, 3H), 4.24(s, 3H), 4.25(s, 3H), 7.93(t, 2H), 6.96(s, 1H),7.20(s, 1H), 7.91(d, 1H), 9.94(s, 1H)

¹³C-NMR (CD₃OD,75 MHz), δ: 18.66, 28.51, 56.72, 56.99, 57.44, 58.12,62.74, 111.29, 114.46, 120.84, 120.95, 121.93, 126.45, 130.12, 132.36,134.23, 137.05, 144.50, 145.51, 148.31, 150.77, 151.80

Positive FAB M/S: m/e 366(Base peak)

IR(KBr) cm⁻¹l: 3410, 1381, 1254, 1112, 1020

7,8,13,13α-tetrahydrocoridaline obtained from the above procedure wasdissolved in DMSO and was determined for its activity on sterol14-reductase. As the result, 50% of inhibitory effect was observed whenthe assay contained 40˜50 μmol/ml of the active ingredient.

EXAMPLE 5 Effect of Dehydrocoridaline Derivatives on Sterol 14-reductaseActivity

Ethylpalmatine (compound no. 8) prepared in Synthetic Example 8 belowwas determined for its inhibitory activity against sterol 14-reductaseas the same manner in Example 4. As a result, 50% of inhibitory effectwere observed when the assay contained 0.1˜3 μmol/ml of the activeingredient.

EXAMPLE 6 Effect of Dehydrocoridaline Derivatives on CholesterolBiosynthesis in Cultured Human Liver Cell Line (HepG2 Cells)

Cultured human liver HepG2 cell line was grown on RPMI (Rosewell parkMemorial Institute) 1640 culture medium containing 10% PBS until 60% ofmonolayer are formed in a 60 mm culture dish. After replacing the mediumwith 3 ml of a fresh culture medium containing 10% (v/v) LPDS (Fetalcalf lipoprotein-deficient serum), the cells were further grown for 48hours until 90% of cultivation degree appear. The culture medium wasremoved and the cell was then washed with PBS. 2 ml of culture mediumcontaining compound no. 8 (final concentration 100 μM) and AY-9944(final concentration 1 μM) were added thereto. Then, the medium wascultivated at 37° C. for 1 hour under the condition of 95% air/5%carbonic acid gas. AY-9944 which is an inhibitor for sterol 7-reductasewas used as a control drug for assuring the present experimentalprocedure on the inhibition of cholesterol biosynthesis. Thereafter, 3μCi of [1,2-⁴C]acetate (72 mCi/mmol) were added thereto. The cultivationwas continued for 2 hours so that the isotope is introduced into thecell and used as a precursor for sterol to be synthesized. Then, theculture medium was completely removed and washed with PBS twice and thecells were collected by scratching. 10 μg of cholesterol, 10 μg oflanosterol and [³H]cholesterol (30,000 dpm) were added thereto, andsaponification reaction was carried out at 70° C. for an hour by adding7.5% of methanolic KOH solution. Unsaponified sterol was removed byextracting them three times with 3 ml of petroleum ether and dried withnitrogen purging. The dried samples were redissolved in 200 μl ofchloroform. An aliquot of the samples was loaded onto Silicagel 60 Fthin layer plate and then separated using ethyl acetate/hexane 25/75(v/v) as the developing solvent. The thin layer film was developed byexposure to Amersham Hyperfilm at −70° C. for 7 days. Cholesterol bandwere confirmed by comparing the band appeared in the film and thatappeared in the iodine-stained thin layer. After scratching thecholesterol band, it was quantified by a liquid scintillation counter.

EXAMPLE 7 In Vivo Effect of Dehydrocoridaline Derivatives on CholesterolBiosynthesis in Syrian Golden Hamster

Male Syrian Golden Hamsters weighing 90˜110 g distributed from SamyukAnimal Laboratory, Seoul, Korea were bred under the followingconditions: They were maintained under reverse light cycle (light cycle:from 6 P.M to 6 A.M; dark cycle: from 6 A.M. to 6 P.M.). The food andwater were supplied at 10 A.M. The commercially available standardrodent chows were used. The hamsters were divided into 6 or 7 animalsper group. The animals were fasted for 12 hours before administratingthe drug. Then, dehydrocoridaline derivatives dissolved in a 0.25%methyl cellulose solution was administered orally for 14 days at theindicated time per a day. After fasting animals for 24 hours from thelast administration, blood was extracted using a cardiac puncture andplasma was then isolated. Plasma lipids, i.e., total cholesterol,LDL-cholesterol, HDL-cholesterol and triglyceride values were analyzedusing Automatic Analyzer (Hitachi 7150).

EXAMPLE 8 Preparation of Pharmaceutically Available Tablets ofDehydrocoridaline Derivatives

The raw drug materials corresponding to an amount of 10,000 tablets wereweighted and passed into 20 mesh sieve and the mixture was then blendedfor 10 minutes. The mixture was transferred to a compressor and wastableted under suitable pressure so as to give average weight of 200 mgper tablet.

1) Composition of the raw drug materials per tablet (200 mg)

Component amount Compound No. 8 10 mg Calcium carboxymethyl cellulose 5mg Lactose #100 (100 mesh) 147.5 mg Hydroxypropyl cellulose 5 mgLudipress (BASF AG) 30 mg Magnesium stearate 2.5 mg

2) Composition of the raw drug materials per tablet (200 mg)

Component amount Compound No. 8 10 mg Calcium carboxymethyl cellulose 5mg Lactose #100 (100 mesh) 147.5 mg Hydroxypropyl cellulose 5 mgKollidon VA64 (BASF AG) 30 mg Magnesium stearate 2.5 mg

3) Composition of the raw drug materials per tablet (200 mg)

Component amount Compound No. 37 5 mg Calcium carboxymethyl cellulose 5mg Lactose #100 (100 mesh) 152.5 mg Hydroxypropyl cellulose 5 mgLudipress (BASF AG) 30 mg Magnesium stearate 2.5 mg

4) Composition of the raw drug materials per tablet (200 mg)

Component amount Compound No. 37 5 mg Calcium carboxymethyl cellulose 5mg Lactose #100 (100 mesh) 152.5 mg Hydroxypropyl cellulose 5 mgKollidon VA64 (BASF AG) 30 mg Magnesium stearate 2.5 mg

5) Composition of the raw drug materials per tablet (200 mg)

Component amount Compound No. 46 2 mg Calcium carboxymethyl cellulose 5mg Lactose #100 (100 mesh) 155.5 mg Hydroxypropyl cellulose 5 mgLudipress (BASF AG) 30 mg Magnesium stearate 2.5 mg

6) Composition of the raw drug materials per tablet (200 mg)

Component amount Compound No. 46 2 mg Calcium carboxymethyl cellulose 5mg Lactose #100 (100 mesh) 155.5 mg Hydroxypropyl cellulose 5 mgKollidon VA64 (BASF AG) 30 mg Magnesium stearate 2.5 mg

Synthetic Examples

Hereinbelow, synthetic examples for the derivative of the compoundsrepresented by the above formula (1) will be described.

EXAMPLE 1 Preparation of 13-methylberberine (Compound No. 1)

3 G of 8-acetonyldihydroberberine and 15 ml of methyl iodide weredissolved in 100 ml of dichloromethane and reacted for 3 hours in anautoclave by heating to 100° C. The undissolved by-products werefiltered off and the filtrate was distilled under reduced pressure toremove the solvent and the remaining methyl iodide. The residue was thenrecrystallized from methanol to give 1.53 g of titled compound as ayellow crystal (m.p.: 168° C.).

¹H-NMR (300 MHz, DMSO-d₆)δ: 2.92(s, 3H), 3.15(m, 2H), 4.09(s, 3H),4.10(s, 3H), 4.80(m, 2H), 6.18(s, 2H), 7.15(s, 1H), 7.48(s, 1H), 8.19(d,J=9.0 Hz, 1H), 8.20(d, J=9.0 Hz, 1H), 9.89(s, 1H)

EXAMPLE 2 Preparation of 2,3-dihydroxy-13-methylberberine (Compound No.2)

0.4 G of 13-methylberberine and 1.2 g of anhydrous aluminum chloridewere poured into a 100 ml round bottom flask. After dissolving themixture by adding 40 ml of benzene into the flask, the solution wasrefluxed for 5 hours. Then, benzene was distilled off under reducedpressure. 40 ml of 1.2 N hydrochloric acid was added to the mixture andthe resulting reaction mixture was refluxed for 1 hour. After coolingthe reaction mixture, the precipitate produced was filtered and thenrecrystallized from methanol to give 0.16 g of titled compound as lightorange crystal (m.p.: 145° C.)

¹H-NMR (300 MHz, DMSO-d₆) δ: 2.91(s, 3H), 3.02(m, 2H), 3.84(s, 3H),4.03(s, 3H), 4.74(m, 2H), 6.90(s, 1H), 7.33(s, 1H), 7.80(d, J=9.0 Hz,1H), 8.05(d, J=9.0 Hz, 1H), 9.82(s, 1H), 10.05(s, 1H)

EXAMPLE 3 Preparation of 2,3,9,10-tetrahydroxyberberine (Compound No. 3)

0.4 G of berberine and 2g of anhydrous aluminum chloride were pouredinto a 100 ml round bottom flask. After dissolving the mixture by adding40 ml of o-xylene into the flask, the solution was refluxed for 3 hours.Then, o-xylene was distilled off under reduced pressure. 40 ml of 1.2 Nhydrochloric acid was added to the mixture and the resulting reactionmixture was refluxed for 1 hour. After cooling the reaction mixture, theprecipitate produced was filtered and recrystallized from methanol togive 0.24 g of the titled compound as a light orange crystal (m.p.: 163°C.).

¹H-NMR (300 MHz, CD₃OD) δ: 3.15(m, 2H), 4.75(m, 2H), 6.80(s, 1H),7.47(s, 1H), 7.60(d, J=9.0 Hz, 1H), 7.72(d, J=9.0 Hz, 1H), 8.43(s, 1H),9.66(s, 1H)

EXAMPLE 4 Preparation of 2,3,9,10-tetrahydroxy-13-methylberberine(Compound No. 4)

0.6 G of 13-methylberberine and 3 g of anhydrous aluminum chloride wereintroduced into a 100 ml round bottom flask and then dissolved in 50 mlof toluene. After the solution was refluxed for 1 hour, toluene wasdistilled off under reduced pressure. 200 ml of 0.8 N hydrochloric acidwas added thereto and the solution was refluxed for 1 hour. Theprecipitate produced after cooling the reaction mixture was filtered andthen recrystallized from methanol to give 0.3 g of the titled compoundas a light orange crystal (m.p.: 255° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 2.84(s, 3H), 3.00(m, 2H), 4.74(m, 2H),6.86(s, 1H), 7.28(s, 1H), 7.72(d, J=9.0 Hz, 1H), 7.86(d, J=9.0 Hz, 1H),9.40(s, 1H), 9.79(s, 1H), 9.87(s, 1H), 10.83(br, 1H)

EXAMPLE 5 Preparation of 2,3,9,10-tetraethoxy-13-ethylberberine(Compound No. 5)

1.1 G of 2,3,9,10-tetrahydroxy-13-ethylberberine and 3.74 g of ethyliodide were introduced into a 100 ml round bottom flask and thendissolved in 50 ml of acetonitrile. After 2.5 g of potassium carbonatewere added thereto, the solution was refluxed for 5 hours. Undissolvedby-products were filtered off and the filtrate was concentrated underreduced pressure to remove acetonitrile. The residue was adsorbed oncelite, and then, purified by column chromatography eluting withmethano/dichloromethane (1:10) to give 0.75 g of the titled compound asa white crystal (m.p.: 255° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 1.39(s, 3H), 1.46(m, 2H), 3.12(m, 2H),4.13(m, 12H), 4.41(m, 8H), 4.91(m, 2H), 7.19(s, 1H), 7.29(s, 1H),8.19(d, 2H), 9.82(s, 1H)

EXAMPLE 6 Preparation of 13-ethylberberine (Compound No. 6)

1.5 G of 8-acetonylberberine and 7.5 ml of ethyl bromide were dissolvedin 100 ml of dichloromethane. The solution was then heated to 100° C. inan autoclave for 5 hours. Undissolved by-products were filtered off, andfiltrate was concentrated under reduced pressure to remove solvent andthe remaining ethyl bromide. The residue was recrystallized frommethanol to give 0.83 g of the titled compound as a white crystal (m.p.:230° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.47(t, J=7.5 Hz, 3H), 3.09(m, 2H), 3.36(q,J=7.5 Hz, 2H), 4.10(s, 6H), 4.80(m, 2H), 6.19(s, 2H), 7.17(s, 1H),7.30(s, 1H), 8.21(ABq, J=9.0 Hz, 2H), 9.90(s, 1H)

EXAMPLE 7 Preparation of 2,3,9,10-tetrahydroxy-13-ethylberberine(Compound No. 7)

7.0 G of 13-ethylberberine and 21.0 g of anhydrous aluminum chloridewere introduced into a 250 ml round bottom flask and then dissolved in100 ml of toluene. After the solution was refluxed for 3 hours, toluenewas distilled off under reduced pressure. 200 ml of 7% hydrochloric acidwas added thereto and the solution was refluxed for 1 hour. Theprecipitate produced after cooling the reaction mixture was filtered andthen recrystallized from methanol to give 2.56 g of the titled compoundas a light orange crystal (m.p.: 280° C.).

¹H-NMR (300MHz, DMSO-d₆) δ: 1.54(t, J=7.5 Hz, 3H), 2.98(m, 2H), 3.25(q,J=7.5 Hz, 2H), 4.75(m, 2H), 6.86(s, 1H), 7.26(s, 1H), 7.78(d, J=8.7 Hz,1H), 7.87(d, J=8.7 Hz, 1H), 9.52(br, 1H), 9.80(s, 1H), 9.83(br, 1H),10.81(br, 1H), 10.90(br, 1H)

EXAMPLE 8 Preparation of 13-ethylpalmatine (Compound No. 8)

1 G of 8-acetonyldihydropalmatine and 20 ml of ethyl iodide weredissolved in 100 ml of dichloromethane in a 250 ml round bottom flask.The solution was then refluxed for 3 hours. Undissolved by-products werefiltered off, and the filtrate was concentrated under reduced pressureto remove excess ethyl iodide and solvent. The residue wasrecrystallized from methanol to give 0.55 g of the titled compound as ayellow crystal (m.p.: 186° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 1.69(t, J=7.5 Hz, 3H), 3.20(m. 2H), 3.3⁶(q,J=7.5 Hz, 2H), 3.71(m, 2H), 3.96(s, 3H), 4.00(s, 3H), 4.13(s, 3H),4.25(s, 3H), 4.95(m, 2H), 7.00(s, 1H), 7.28(s, 1H), 8.03(d, J=9.0 Hz,2H), 8.08(d, J=9.0 Hz, 1H), 10.00(s, 1H)

EXAMPLE 9 Preparation of 13-allylberberine (Compound No. 9)

4.2 G of 8-acetonyldihydroberberine and 11 ml of allyl iodide weredissolved in 100 ml of dichloromethane in a 250 ml round bottom flask.The solution was then refluxed for 5 hours. Undissolved by-products werefiltered off, and the filtrate was concentrated under reduced pressureto remove excess allyl iodide and solvent. The residue wasrecrystallized from methanol to give 1.72 g of the titled compound as adark brown crystal (m.p.: 186° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 3.13(m, 2H), 4.08(m, 2H), 4.08(s, 3H),4.12(s, 3H), 4.85(m, 2H), 4.89(d, J=10.2 Hz, 1H), 5.38(d, J=10.2 Hz,1H), 6.17(s, 2H), 6.45(m, 1H), 7.18(s, 1H), 7.36(s, 1H), 8.01(d, J=9.0Hz, 1H), 8.20(d, J=9.0 Hz, 1H), 9.98(s, 1H)

EXAMPLE 10 Preparation of 2,3,9,10-tetrahydroxy-13-allylberberine(Compound No. 10)

1.0 G of 13-allylberberine and 3.0g of anhydrous aluminum chloride wereintroduced into a 50 ml round bottom flask and then dissolved in 20 mlof toluene. After the solution was refluxed for 5 hours, toluene wasdistilled off under reduced pressure. 40 ml of 7% hydrochloric acid wasadded thereto and the solution was refluxed for 1 hour. The precipitateproduced after cooling the reaction mixture was filtered andrecrystallized from methanol to give 0.43 g of the titled compound as alight orange crystal (m.p.: 234° C.).

¹H-NMR (300 MHz, CD₃OD) δ: 3.23(m, 2H), 4.08(m, 2H), 4.60(m, 2H),5.12(d, J=10.2 Hz, 1H), 5.16(d, J=10.2 Hz, 1H), 6.71(s, 1H), 6.80(m,1H), 7.76(s, 1H), 7.83(ABq, 2H), 8.86(s, 1H), 9.67(s, 1H), 10.22(s, 1H),10.70(s, 1H), 10.78(s, 1H)

EXAMPLE 11 Preparation of 13-n-propylpalmatine (Compound No. 11)

0.5 G of 8-acetonyldihydropalmatine and 0.43 g of propyl iodide wereintroduced into a 100 ml round bottom flask and then dissolved in 50 mlof dioxane. The solution was refluxed for 4 hours. Undissolvedby-products were filtered off and the filtrate was then concentratedunder reduced pressure to remove dioxane. The residue was adsorbed oncelite, and then, purified by column chromatography eluting withmethanol/dichloromethane (1:10) to give 0.25 g of the titled compound asa yellow crystal (m.p.: 190° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.05(t, J=7.0 Hz, 3H), 1.10(m, 2H), 1.83(m,2H), 3.08(m, 2H), 3.87(s, 3H), 3.89(s, 3H), 4.09(s, 3H), 4.10(s, 3H),4.92(m, 2H), 7.19(s, 1H), 7.23(s, 1H), 8.20(ABq, 2H), 9.96(s, 1H)

EXAMPLE 12 Preparation of 13-n-butylpalmatine (Compound No. 12)

1.0 G of 8-acetonyldihydropalmatine and 9.2 g of butyl iodide wereintroduced into a 50 ml round bottom flask and then dissolved in 10 mlof acetonitrile. The solution was refluxed for 5 hours. Undissolvedby-products were filtered off and the filtrate was then concentratedunder reduced pressure to remove acetonitrile. The residue was adsorbedon celite, and then, purified by column chromatography eluting withmethanol/dichloromethane (1:10) to give 0.42 g of the titled compound asa yellow crystal (m.p.: 170° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.95(t, J=7.5 Hz, 3H), 1.47(m, 2H), 1.82(m,2H), 3.14(m. 2H), 3.31(m, 2H), 3.81(s, 3H), 3.84(s, 3H), 4.01(s, 6H),4.83(m, 2H), 7.20(s, 1H), 7.31(s, 1H), 8.23(ABq, 2H), 9.89(s, 1H)

EXAMPLE 13 Preparation of 13-(cyclopropylmethyl)palmatine (Compound No.13)

1.0 G of 8-acetonyldihydropalmatine, 6.7 g of cyclopropylmethyl bromideand 1.14 g of sodium iodide were introduced into a 50 ml round bottomflask and then dissolved in 10 ml of acetonitrile. The solution wasrefluxed for 3 hours. Undissolved by-products were filtered off, and thefiltrate was then concentrated under reduced pressure to removeacetonitrile. The residue was adsorbed on celite, and then, purified bycolumn chromatography eluting with methanol/dichloromethane (1:10) togive 0.37 g of the titled compound as a yellow crystal (m.p.: 230° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 0.42(m, 2H), 0.78(m, 2H), 1.04(m, 1H),3.25(m, 2H), 3.38(d, J=6.0 Hz, 2H), 3.98(s, 3H), 4.00(s, 3H), 4.05(s,3H), 4.41(s, 3H), 5.18(m, 2H), 6.96(s, 1H), 7.45(s, 1H), 7.89(d, J=9.0Hz, 1H), 8.17(d, J=9.0 Hz, 1H), 10.32(s, 1H)

EXAMPLE 14 Preparation of 13-n-octylpalmatine (Compound No.14)

1.0 G of 8-acetonyldihydropalmatine, 9.6 g of octyl bromide and 1.14 gof sodium iodide were introduced into a 50 ml round bottom flask andthen dissolved in 10 ml of acetonitrile. The solution was refluxed for 3hours. Undissolved by-products were filtered off and the filtrate wasthen concentrated under reduced pressure to remove acetonitrile. Theresidue was adsorbed on celite, and then, purified by columnchromatography eluting with methanol/dichloromethane (1:10) to give 0.43g of the titled compound as a yellow crystal (m.p.: 128° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 0.89(t, J=7.0 Hz, 3H), 1.28(m, 6H), 1.63(m,4H), 1.98(m, 2H), 3.27(m, 4H), 3.94(s, 3H), 4.01(s, 3H), 4.06(s, 3H),4.40(s, 3H), 5.19(m, 2H), 6.95(s, 1H), 7.21(s, 1H), 7.88(ABq, 2H),10.38(s, 1H)

EXAMPLE 15 Preparation of 13-(cyclohexylmethyl)palmatine (Compound No.15)

1.0 G of 8-acetonyldihydropalmatine, 8.8 g of cyclohexylmethyl bromideand 1.14 g of sodium iodide were introduced into a 50 ml round bottomflask and then dissolved in 10 ml of acetonitrile. The solution wasrefluxed for 3 hours. Undissolved by-products were filtered off andfiltrate was then concentrated under reduced pressure to removeacetonitrile. The residue was adsorbed on celite, and then, purified bycolumn chromatography eluting with methanol/dichloromethane (1:10) togive 0.47 g of the titled compound as a yellow crystal (m.p.: 198° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 0.99˜1.62(m, 11H), 3.21(m, 2H), 3.46(d, J=7.5Hz, 2H), 3.89(s, 3H), 4.01(s, 3H), 4.10(s, 3H), 4.40(s, 3H), 5.17(m,2H), 6.94(s, 1H), 7.21(s, 1H), 7.87(ABq, 2H), 7.81(m, 1H), 10.38(s, 1H)

EXAMPLE 16 Preparation of 13-iodopropylpalmatine (Compound No.16)

1.0 G of 8-acetonyldihydropalmatine, and 7.4 g of 1,3-diiodopropane wereintroduced into a 50 ml round bottom flask and then dissolved in 30 mlof acetonitrile. The solution was refluxed for 6 hours. Undissolvedby-products were filtered off and the filtrate was then concentratedunder reduced pressure to remove acetonitrile. The residue was adsorbedon celite, and then, purified by column chromatography eluting withmethanol/dichloromethane (1:10) to give 0.6 g of the titled compound asa brown crystal (m.p.: 156° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 2.34(m, 2H), 3.26(m, 4H), 3.58(m, 2H),3.98(s, 3H), 4.01(s, 3H), 4.09(s, 3H), 4.38(s, 3H), 5.10(m, 2H), 6.92(s,1H), 7.20(s, 1H), 7.88(d, J=9.0 Hz, 1H), 7.98(d, J=9.0 Hz, 1H), 10.32(s,1H)

EXAMPLE 17 Preparation of 2,3,9,1 0-tetra-n-butoxyprotoberberine(Compound No.17)

2.0 G of 2,3,9,10-tetrahydroxyberberine and 9.1 g of butyl iodide wereintroduced into a 250 ml round bottom flask and then dissolved in 100 mlof acetonitrile. 5.34 G of potassium carbonate were added thereto andthe solution was then refluxed for 7 hours. Undissolved by-products werefiltered off and the filtrate was then concentrated under reducedpressure to remove acetonitrile. The residue was adsorbed on celite, andthen, purified by column chromatography eluting withmethanol/dichloromethane (1:10) to give 1.51 g of the titled compound asa yellow crystal (m.p.: 180° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.02(t, J=7.5 Hz, 12H), 1.48˜1.62(m, 4H),1.80˜2.04(m, 4H), 3.30(m, 2H), 4.12(t, J=7.5 Hz, 2H), 4.18(t, J=7.5 Hz,2H), 4.19(t, J=7.5 Hz, 2H), 4.51(t, J=7.5 Hz, 2H), 5.10(m, 2H), 6.72(s,1H), 7.39(s, 1H), 7.68(d, J=9.0 Hz, 1H), 7.98(d, J=9.0 Hz, 1H), 8.52(s,1H), 9.88(s, 1H)

EXAMPLE 18 Preparation of 13-(1,3-dioxane-2-yl)ethylpalmatine (CompoundNo. 18)

1.0 G of 8-acetonyldihydropalmatine and 3.4 ml of2-(bromoethyl)-1,3-dioxane were introduced into a 50 ml round bottomflask and then dissolved in 20 ml of acetonitrile. The solution wasrefluxed for 6 hours. Undissolved by-products were filtered off and thefiltrate was then concentrated under reduced pressure to removeacetonitrile. The residue was adsorbed on celite, and then, purified bycolumn chromatography eluting with methanol/dichloromethane (1:10) togive 0.62 g of the titled compound as a yellow crystal (m.p.: 146° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.37(d, J=13.5 Hz, 1H), 1.84(m, 1H),2.08(m, 2H), 3.11(m. 2H), 3.43(m, 2H), 3.73(t, J=13.5 Hz, 2H), 3.89(s,6H), 4.00˜4.05(m, 2H), 4.09(s, 3H), 4.11(s, 3H), 4.78(m, 3H), 7.18(s,1H), 7.32(s, 1H), 8.16(d, J=9.6 Hz, 1H), 8.26(d, J=9.6 Hz, 1H), 9.92(s,1H)

EXAMPLE 19 Preparation of 13-ethoxycrbonylpalmatine (Compound No. 19)

1.0 G of 8-acetonyldihydropalmatine, and 2.65 g of ethyl chloroformatewere introduced into a 50 ml round bottom flask and then dissolved in 10ml of acetonitrile. The solution was refluxed for 6 hours. Undissolvedby-products were filtered off and the filtrate was then concentratedunder reduced pressure to remove acetonitrile. The residue was adsorbedon celite, and then, purified by column chromatography eluting withmethanol/dichloromethane (1:10) to give 0.28 g of the titled compound asa yellow crystal (m.p.: 92° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 1.19(t, J=7.5 Hz, 3H), 3.38(m, 2H), 3.88(s,3H), 4.02(s, 3H), 4.08(s, 3H), 4.40(q, J=7.5 Hz, 2H), 4.42(s, 3H),5.38(m, 2H), 6.89(s, 1H), 7.21(s, 1H), 7.73(d, J=9.0 Hz, 1H), 7.88(d,J=9.0 Hz, 1H), 10.82(s, 1H)

EXAMPLE 20 Preparation of 13-ethoxycarbonylmethylpalnatine (Compound No.20)

1.0 G of 8-acetonyldihydropalmatine, and 3.0 ml of ethyl chloroacetatewere introduced into a 100 ml round bottom flask and then dissolved in50 ml of acetonitrile. The solution was refluxed for 6 hours.Undissolved by-products were filtered off and the filtrate was thenconcentrated under reduced pressure to remove acetonitrile. The residuewas adsorbed on celite, and then, purified by column chromatographyeluting with methanol/dichloromethane (1:10) to give 0.25 g of thetitled compound as a yellow crystal (m.p.: 200° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.25(t, J=7.2 Hz, 3H), 2.02(m,2H), 3.18(m,2H), 3.77(s, 3H), 3.90(s, 3H), 4.10(s, 3H), 4.12(s, 3H), 4.23(q, J=7.2Hz, 2H), 4.51(s, 2H), 4.88(m, 2H), 7.21(s, 1H), 7.22(s, 1H), 8.02(d,J=9.0 Hz, 1 H), 8.23(d, J=9.0 Hz, 1 H), 10.00(s, 1 H)

EXAMPLE 21 Preparation of 13-carboxymethylpalmatine (Compound No. 21)

0.45 G of 13-ethoxycarbonylpalmatine and 0.5 g of sodium hydroxide wereintroduced into a 50 ml round bottom flask and then dissolved in 30 mlof 80% methanol. The solution was refluxed for 4 hours. Concentratedhydrochloric acid was added dropwise thereto until the solution becomeacidic and then the solution was extracted with dichlorometiane. Theextract was dried with magnesium sulfate, filtered and concentrated. Theresidue was purified by column chromatography eluting withmethanol/dichloromethane (1:10) to give 0.15 g of the titled compound asa faint yellow crystal (m.p.: 198° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 3.18(m, 2H), 3.78(s, 3H), 3.84(s, 3H),4.08(s, 3H), 4.10(s, 3H), 4.37(s, 2H), 4.83(m, 2H), 7.20(s, 1H), 7.30(s,1H), 8.06(d, J=9.0 Hz, 1H), 8.23(d, J=9.0 Hz, H), 9.98(s, 1H)

EXAMPLE 22 Preparation of 13-(1-methoxycarbonylethyl)berberine (CompoundNo. 22)

1.0 G of 8-acetonyldihydroberberine, and 4.2 g of methyl2-bromopropionate were introduced into a 100 ml round bottom flask andthen dissolved in 50 ml of chloroform. The solution was refluxed for 3hours. Undissolved by-products were filtered off and the filtrate wasthen concentrated under reduced pressure to remove chloroform. Theresidue was adsorbed on celite, and then, purified by columnchromatography eluting with methanol/dichloromethane (1:10) to give 0.38g of the titled compound as a light yellow crystal (m.p.: 187° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.58(d, J=7.5 Hz, 3H), 3.10(m, 2H), 4.03(s,3H), 4.09(s, 3H), 4.64(m, 1H), 4.98(m, 2H), 6.19(s, 2H), 7.18(s, 1H),7.27(s, 1H), 7.78(d, J=9.0 Hz, 1H), 8.23(d, J=9.0 Hz, 1H), 9.98(s, 1H)

EXAMPLE 23 Preparation of 13-α-(γ-lactonyl)berberine (Compound No. 23)

1.0 G of 8-acetonyldihydroberberine and 4.2 g of α-bromo-butyrolactonewere introduced into a 100 ml round bottom flask and then dissolved in50 ml of chloroform. The solution was refluxed for 3 hours. Undissolvedby-products were filtered off and the filtrate was then concentratedunder reduced pressure to remove chloroform. The residue was adsorbed oncelite, and then, purified by column chromatography eluting withmethanol/dichloromethane (1:10) to give 0.32 g of the titled compound asa yellow crystal (m.p.: 240° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 2.67(m, 2H), 3.12(m, 2H), 4.06(s, 3H),4.09(s, 3H), 4.56(dd, 1H), 4.76(m, 2H), 4.92(m, 1H), 5.12(t, 1H),6.19(s, 2H), 7.22(s, 1H), 7.24(s, 1H), 7.65(d, J=9.0 Hz, 1H), 8.24(d,J=9.0 Hz, 1H), 10.00(s, 1H)

EXAMPLE 24 Preparation of 13-ethoxycarbonylmethylberberine (Compound No.24)

1.0 of 8-acetonyldihydroberberine, 3.0 g of ethyl chloroacetate, and3.75 g of sodium iodide were introduced into a 100 ml round bottom flaskand then dissolved into 50 ml of chloroform. The solution was refluxedfor 4 hours. Undissolved by-products were filtered off and the filtratewas then concentrated under reduced pressure to remove chloroform. Theresidue was adsorbed on celite, and then, purified by columnchromatography eluting with methanol/dichloromethane (1:10) to give 0.53g of the titled compound as a pale yellow crystal (m.p.: 165° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.22(t, J=7.5 Hz, 3H), 3.10(m, 2H), 4.08(s,3H), 4.12(s, 3H), 4.23(q, J=7.5 Hz, 3H), 4.45(s, 2H), 4.82(m, 2H),6.21(s, 2H), 7.18(s, 1H), 7.10(s, 1H), 8.01(d, J=9.0 Hz, 1H), 8.23(d,J=9.0 Hz, 1 H), 10.00(s, 1H)

EXAMPLE 25 Preparation of9-hydroxyethylamino-13-ethylberberine (CompoundNo. 25)

0.5 G of 13-ethylpalmatine and 5 ml of ethanolamine were introduced intoa 50 ml round bottom flask and then dissolved in 15 ml of ethanol. Thesolution was refluxed for 5 hours. Ethanol and unreacted ethanolaminewere distilled off under reduced pressure. The residue was extractedwith dichloromethane and then concentrated to remove solvent. Theresulting residue was adsorbed on celite, and then, purified by columnchromatography eluting with methanol/dichloromethane (1:10) to give 0.16g of the titled compound as a brown crystal (m.p.: 214° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.51(t, J=7.5 Hz, 3H), 2.98(m, 2H), 3.12(m,2H), 3.40(m, 4H), 3.78(s, 3H), 3.85(s, 3H), 3.86(s, 3H), 4.45(m, 2H),6.64(d, J=9.0 Hz, 1H), 7.08(s, 1H), 7.21 (s, 1H), 7.38(d, J=9.0 Hz, 2H),9.22(s, 1H)

EXAMPLE 26 Preparation of 8-acetonyldihydroberberine (Compound No. 26)

2.5 G of berberine, 2.5 ml of water and 13 ml of acetone were introducedinto a 100 ml round bottom flask and a 50% sodium hydroxide solution wasadded dropwise to the mixture. The resulting reaction mixture wasstirred at room temperature for 10 minutes. The precipitate was filteredand recrystallized from methanol to give 2.06 g of the titled compoundas a brown crystal (m.p.: 130° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 2.03(s, 3H), 2.30(dd, J=4.8, 14.4 Hz, 1H),2.74(m, 2H), 2.93(dd, J=6.6, 14.4 Hz, 1H), 3.24(m, 3H), 3.76(s, 3H),3.77(s, 3H), 5.21(dd, J=4.8, 6.6 Hz, 1H), 5.99(s, 2H), 6.00(s, 1H),6.72(d, J=8.4 Hz, 1H), 6.75(s, 1H), 6.86(d, J=8.4 Hz, 1H), 7.24(s, 1H)

EXAMPLE 27 Preparation of 8-methyldihydroberberine (Compound No. 27)

2.0 G of berberine, 2.13 g of methyl iodide, and 0.37 g of magnesiumwere introduced into a 250 ml round bottom flask and then dissolved in150 ml of anhydrous ether. After refluxing for 1 hour, the solution wasdried. Distilled water was then added to it while stirring. After theresulting solution was filtered, the filtrate was freeze dried. Theresidue was extracted with dichloromethane and then distilled off underreduced pressure to remove the solvent. 1.13 g of the titled compoundwas obtained as a dark green crystal (m.p.: 96° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.06(d, J=6.3 Hz, 3H), 2.79(m, 3H), 3.30(m,2H), 3.77(s, 3H), 3.78(s, 3H), 4.81(q, 1H), 5.93(s, 1H), 5.99(d, 2H),6.68(d, J=8.7 Hz, 1H), 6.77(s, 1H), 6.82(d, J=8.7 Hz, 1H), 7.25(s, 1H)

EXAMPLE 28 Preparation of 8-ethyldihydroberberine (Compound No. 28)

2.0 G of berberine, 1.51 ml of ethyl iodide, and 0.45 g of magnesiumwere introduced into a 250 ml round bottom flask and then dissolved in150 ml of anhydrous ether. After refluxing for 1 hour, the solution wasdried. Distilled water was then added to it while stirring. After theresulting solution was filtered, the filtrate was freeze dried. Theresidue was extracted with dichloromethane and the solvent was thendistilled off under reduced pressure. 1.42 g of the titled compound wasobtained as a dark brown crystal (m.p.: 90° C.

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.72(t, J=7.5 Hz, 3H), 1.61(m, 2H), 2.76(m,2H), 3.30(m, 2H), 3.76(s, 6H), 4.63(dd, 1H), 5.83(s, 1H), 5.99(d, J=1.2Hz, 1H), 6.00(d, J=1.2 Hz, 1H), 6.67(d, J=8.1 Hz, 1H), 6.77(s, 1H),6.83(d, J=8.1 Hz, 1H), 7.22(s, 1H)

EXAMPLE 29 Preparation of 8-n-propyldiydroberberine (Compound No. 29)

2.0 G of berberine, 1.8 ml of propyl iodide, and 0.457 g of magnesium ina 250 ml round bottom flask were well mixed with 150 ml of anhydrousether. After refluxing for 1 hour, the solution was dried. Distilledwater was then added to it while stirring. After the resulting solutionwas filtered, the filtrate was freeze dried. The residue was extractedwith dichloromethane and the solvent was then distilled off underreduced pressure to give 1.3 g of the titled compound as a yellowcrystal (m.p.: 90° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.76(t, J=7.5 Hz, 3H), 1.18(m, 2H), 1.58(m,2H), 2.75(m, 2H), 3.31(m, 2H), 3.77(s, 6H), 4.67(dd, 1H), 5.85(s, 1H),5.99(d, J=1.2 Hz, 1H), 6.00(d, J=1.2 Hz, 1H), 6.67(d, J=8.4 Hz, 1H),6.76(s, 1H), 6.82(d, J=8.4 Hz, 1H), 7.23(s, 1H)

EXAMPLE 30 Preparation of 8-n-butyldihydroberberine (Compound No. 30)

2.0 G of berberine, 1.90 ml of butyl chloride and 0.37 g of magnesium ina 250 ml round bottom flask were well mixed with 150 ml of anhydrousether and then refluxed for 3 hours. After drying the solution,distilled water was then added to it while stirring. After the resultingsolution was filtered, the filtrate was freeze dried. The residue wasextracted with dichloromethane and the solvent was then distilled offunder reduced pressure to give 1.24 g of the titled compound as a browncrystal (m.p.: 68° C.)

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.75(t, J=7.5 Hz, 3H), 1.17(m, 4H), 1.59(m,2H), 2.79(m, 2H), 3.30(m, 2H), 3.77(s, 6H), 4.67(dd, 1H), 5.86(s, 1H),5.99(d, J=0.6 Hz, 1H), 6.00(d, J=0.6 Hz, 1H), 6.67(d, J=8.1 Hz, 1H),6.76(s, 1H), 6.82(d, J=8.1 Hz, 1H), 7.23(s, 1H)

EXAMPLE 31 Preparation of 8-cyclohexylmethyldihydroberberine (CompoundNo. 31)

2.0 G of berberine, 2.51 ml of cyclohexylmethyl bromide and 0.37 g ofmagnesium in a 250 ml round bottom flask were well mixed with 150 ml ofanhydrous ether, and then, refluxed for 1 hour. After drying thesolution, distilled water was then added to it while stirring. After theresulting solution was filtered, the filtrate was freeze dried. Theresidue was extracted with dichloromethane and the solvent was thendistilled off under reduced pressure to give 1.66 g of the titledcompound as a brown crystal. (m.p.: 107° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.82(m, 2H), 1.14(m, 8H), 1.63(m, 2H),2.81(m, 3H), 3.32(m, 2H), 3.76(s, 3H), 3.78(s, 3H), 4.62(dd, 1H),5.92(s, 1H), 5.99(d, 2H), 6.66(d, J=8.1 Hz, 1H), 6.76(s, 1H), 6.81(d,J=8.1 Hz, 1H), 7.23(s, 1H)

EXAMPLE 32 Preparation of 8-i-propyldihydroberberine (Compound No. 32)

2.0 G of berberine, 1.8 ml of isopropyl iodide and 0.37 g of magnesiumin a 250 ml round bottom flask were well mixed with 150 ml of anhydrousether and was then refluxed for 3 hours. After drying the solution,distilled water was then added to it while stirring. After the resultingsolution was filtered, the filtrate was freeze dried. The residue wasextracted with dichloromethane and the solvent was then distilled offunder reduced pressure to give 0.76 g of the titled compound as a browncrystal (m.p.: 98° C.)

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.80(d, J=6.6 Hz, 3H), 0.82(d, J=6.6 Hz,3H), 1.87(m, 1H), 2.68(m, 1H), 2.97(m, 1H), 3.75(s, 3H), 3.77(s, 3H).4.48(d, 1H), 5.89(s, 1H), 5.99(s, 2H), 6.67(d, J=8.1 Hz, 1H), 6.75(s,1H), 6.81(d, J=8.1 Hz, 1H), 7.25(s, 1H)

EXAMPLE 33 Preparation of 8-methyldihydropalmatine (Compound No. 33)

2.0 G of palmatine, 1.21 ml of methyl iodide and 0.45 g of magnesium ina 250 ml round bottom flask were well mixed with 150 ml of anhydrousether, and then, refluxed for 3 hours. After drying the solution,distilled water was then added to it while stirring. After the resultingsolution was filtered, the filtrate was freeze dried. The residue wasextracted with dichloromethane and the solvent was then distilled offunder reduced pressure to give 0.64 g of the titled compound as a browncrystal (m.p.: 75° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 1.02(d, 3H), 2.81(m, 2H), 3.27(m, 2H),3.76(s, 3H), 3.77(s, 3H), 3.78(s, 3H), 3.81(s, 3H), 4.78(q, 1H), 6.00(s,1H), 6.68(d, J=8.1 Hz, 1H), 6.79(s, 1H), 6.81(d, J=8.1 Hz, 1H), 7.20(s,1H)

EXAMPLE 34 Preparation of 8-ethyldihydropalmatine (Compound No. 34)

2.0 G of palmatine, 2.9 ml of ethyl iodide and 0.9 g of magnesium in a250 ml round bottom flask were well mixed with 150 ml of anhydrousether, and then, refluxed for 1hour. After drying the solution,distilled water was then added to it while stirring. After the resultingsolution was filtered, the filtrate was freeze dried. The residue wasextracted with dichloromethane and the solvent was then distilled offunder reduced pressure to give 0.88 g of the titled compound as a browncrystal (m.p.: 86° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.73(t, 3H), 1.61(m, 2H), 2.80(m, 2H),3.47(m, 2H), 3.76(s, 3H), 3.77(s, 3H), 3.78(s, 3H), 3.81 (s, 3H),4.62(m, 1H), 5.89(s, 1H), 6.69(d, J=8.1 Hz, 1H), 6.79(s, 1H), 6.82(d,J=8.1 Hz, 1H), 7.20(s, 1H)

EXAMPLE 35 Preparation of 8-n-octyldihydropalnatine (Compound No. 35)

2.0 G of berberine, 4.2 ml of octyl iodide and 0.45 g of magnesium in a250 ml round bottom flask were well mixed with 150 ml of anhydrousether, and then, refluxed for 3 hours. After drying the solution,distilled water was then added to it while stirring. After the resultingsolution was filtered, the filtrate was freeze dried. The residue wasextracted with dichloromethane and the solvent was then distilled offunder reduced pressure to give 0.92 g of the titled compound as a brownliquid (m.p.: room temperature).

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.84(t, 3H), 1.19(m, 12H), 2.69(m, 2H),2.79(m, 2H), 3.01(m, 2H), 3.74(s, 3H), 3.89(s, 3H), 4.78(dd, 1H),6.06(s, 1H), 6.11(s, 2H), 7.00(s, 1H), 7.11(d, 1H), 7.19(d, 1H), 7.27(s,1H)

EXAMPLE 36 Preparation of 8-cyclopropyldihydropalmatine (Compound No.36)

2.0 G of berberine, 1.42 ml of cyclopropyl iodide and 0.45 g ofmagnesium in a 250 ml round bottom flask were well mixed with 150 ml ofanhydrous ether, and then, refluxed for 3 hours. After drying thesolution, distilled water was then added to it while stirring. After theresulting solution was filtered, the filtrate was freeze dried. Theresidue was extracted with dichloromethane and the solvent was thendistilled off under reduced pressure to give 0.71 g of the titledcompound as a brown crystal (m.p.: 162° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.42(m, 4H), 1.19(m, 1H), 2.80(m, 2H),3.55(m, 2H), 3.73(s, 3H), 3.77(s, 3H), 3.91(m, 1H), 5.99(s, 1H), 6.00(d,2H), 6.72(d, J=8.4 Hz, 1H), 6.77(s, 1H), 6.85(d, J=8.4 Hz, 1H), 7.30(s,1H)

EXAMPLE 37 Preparation of 8-acetonyl- 13-ethyldihydropahnatine (CompoundNo. 37)

10 G of 13-ethylpalmatine, 50 ml of water and 10 ml of acetone wereintroduced into a 100 ml round bottom flask and 15 g of a 50% sodiumhydroxide solution was added dropwise to the reaction mixture. Themixture was stirred at room temperature for 10 minutes. The precipitatewas filtered and recrystallized from methanol to give 8.63 g of thetitled compound as a white crystal (m.p.: 156° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 1.33(t, J=7.2 Hz, 3H), 2.00(s, 3H), 2.23(dd,1H), 2.80(m, 5H), 3.20(m, 1H), 3.33(m, 1H), 3.87(s, 3H), 3.90(s, 3H),3.91(s, 3H), 3.93(s, 3H), 5.12(dd, 1H), 6.67(s, 1H), 6.87(d, J=8.1 Hz,1H), 7.03 (d, J=8.1 Hz, 1H), 710(s, 1H)

EXAMPLE 38 Preparation of 8-(butan-2-one-1 -yl)-13-ethyldihydropalmatine(Compound No. 38)

10 G of 13-ethylpalmatine, 50 ml of water and 12 ml of ethylmethylketonewere introduced into a 100 ml round bottom flask, and 15 g of a 50%sodium hydroxide solution was added dropwise to the mixture. The mixturewas stirred at room temperature for 10 minutes. The precipitate wasfiltered and recrystallized from methanol to give 8.14 g of the titledcompound as a white crystal (m.p.: 127° C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.79(m, 3H), 1.25(m, 3H), 2.25(m, 2H),2.70(m, 6H), 3.01(m, 1H), 3.28(m, 1H), 3.77(s, 3H), 3.78(s, 3H), 3.79(s,3H), 3.80(s, 3H), 5.14(dd, 1H), 6.85(s, 1H), 6.95(d, J=8.1 Hz, 1H),6.96(d, J=8.1 Hz, 1H), 7.00(s, 1H)

EXAMPLE 39 Preparation of 8-(3-methylbutan-2-one-1-yl)-13-ethyldihydropalmatine (Compound No. 39)

10 G of 13-ethylpalmatine, 50 ml of water and 13 ml of i-propylmethylketone were introduced into a 100 ml round bottom flask, and 15 g of a50% sodium hydroxide solution was added dropwise to the mixture. Themixture was stirred at room temperature for 10 minutes. The precipitatewas filtered and recrystallized from methanol to give 7.84 g of thetitled compound as a white crystal (m.p.: 72° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 0.89(d, J=6.9 Hz, 3H), 0.95(d, J=6.9 Hz, 3H),1.33(t, 3H), 2.20(m, 1H), 2.40(m, 1H), 2.79(m, 4H), 3.12(m, 2H), 3.37(m,1H), 3.87(s, 3H), 3.90(s, 3H), 3.90(s, 3H), 3.92(s, 3H), 5.31(dd, 1H),6.66(s, 1H), 6.86(d, J=9.0 Hz, 1H), 7.04(d, J=9.0 Hz, 1H), 7.09(s, 1H)

EXAMPLE 40 Preparationof8-(4-methylpentan-2-one-1-yl)-13-ethyldihydro-palmatine (Compound No.40)

10 G of 13-ethylpalmatine, 50 ml of water and 15 ml ofi-butylmethylketone were introduced into a 100 ml round bottom flask,and 15 g of a 50% sodium hydroxide solution was added dropwise to themixture. The mixture was stirred at room temperature for 10 minutes. Theprecipitate was filtered and recrystallized from methanol to give 7.84 gof the titled compound as a white crystal (m.p.: 127° C.).

¹-NMR (300 MHz, CDCl₃) δ: 0.79(m, 6H), 1.27(t, 3H), 1.97(m, 1H), 2.17(m,2H), 2.25(m, 1H), 2.82(m, 5H), 3.18(m, 1H), 3.36(m, 1H), 3.87(s, 3H),3.91(s, 6H), 3.94(s, 3H), 5.26(dd, J=3.6, 8.1 Hz, 1H), 6.67(s, 1H),6.86(d, J=8.7 Hz, 1H), 7.04(d, J=8.7 Hz, 1H), 7.10(s, 1H)

EXAMPLE 41 Preparation of 8-cyanomethyl-13-ethyldihydropalmatine(Compound No. 41)

10 G of 13-ethylpalmatine, 50 ml of water and 10 ml of acetonitrile wereintroduced into a 100 ml round bottom flask, and 15 g of a 50% sodiumhydroxide solution was added dropwise to the mixture. The mixture wasstirred at room temperature for 10 minutes. The precipitate was filteredand recrystallized from methanol to give 8.09 g of the titled compoundas a white crystal (m.p.: 147° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 1.28(t, 3H), 2.75(m, 6H), 3.51(m, 1H),3.91(s, 6H), 3.92(s, 3H), 3.95(s, 3H), 4.13(m, 1H), 5.61(s, 1H), 6.72(s,1H), 7.03(s, 1H), 7.05(d, J=9.0 Hz, 1H), 7.16(d, J=9.0 Hz, 1H)

EXAMPLE 42 Preparation of8-(cyclopentanon-2-yl)-13-ethyldihydropalmatine (Compound No. 42)

10 G of 13-ethylpalmatine, 50 ml of water and 15 ml of cyclopentanonewere introduced into a 100 ml round bottom flask, and 15 g of a 50%sodium hydroxide solution was added dropwise to the mixture. The mixturewas stirred at room temperature for 10 minutes. The precipitate wasfiltered and recrystallized from methanol to give 7.7 g of the titledcompound as a white crystal (m.p.: 165° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 1.22(t, 3H), 1.80(m, 8H), 2.70(m, 4H),3.23(m, 1H), 3.88(s, 3H), 3.90(s, 3H), 3.94(s, 3H), 3.95(s, 3H), 5.50(d,1H), 6.66(s, 1H), 6.86(d, J=8.7 Hz, 1H), 6.98(d, J=8.7 Hz, 1H), 7.07(s,1H)

EXAMPLE 43 Preparation of 8-(cyclohexanon-2-yl)-13-ethyldihydropalmatine(Compound No. 43)

10 G of 13-ethylpalmatine, 50 ml of water and 15 ml of cyclohexanonewere introduced into a 100 ml round bottom flask, and 15 g of a 50%sodium hydroxide solution was added dropwise to the mixture. The mixturewas stirred at room temperature for 10 minutes. The precipitate wasfiltered and recrystallized from methanol to give 7.46 g of the titledcompound as a white crystal (m.p.: 125° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 1.24(t, 3H), 1.62(m, 5H), 2.30(m, 4H),2.85(m, 4H), 3.20(m, 2H), 3.87(s, 6H), 3.91(s, 3H), 3.92(s, 3H), 5.67(d,J=1.8 Hz, 1H), 6.68(s, 1H), 6.85(d, J=8.7 Hz, 1H), 6.98(d, J=8.7 Hz,1H), 7.03(s, 1H)

EXAMPLE 44 Preparation of 8-acetonyl-13 -ethyl-2,3,9,10-tetraethoxy-dihydroprotoberberine (Compound No. 44)

15 G of 13-ethyl-2,3,9,10-tetraethoxyprotoberberine, 10 ml of water and15 ml of acetone were introduced into a 100 ml round bottom flask, and20 g of a 50% sodium hydroxide solution was added dropwise to themixture. The solution was stirred at room temperature for 10 minutes.The solvent was distilled off under reduced pressure to its half amount.The precipitate was filtered and recrystallized from methanol to give7.06 g of the titled compound as a white crystal (m.p.: 108° C.).

¹H-NMR (300 MHz, CDCl₃) δ: 1.32(t 3H), 1.42(m, 12H), 1.99(s, 3H),2.30(m, 1H), 2.75(m, 4H), 3.20(m, 1H), 4.05(m, 10H), 5.26(dd, J=3.9, 7.5Hz, 1H), 6.66(s, 1H), 6.83(d, J=8.7 Hz, 1H), 7.00(d, J=8.7 Hz, 1H),7.10(s, 1H)

EXAMPLE 45 Preparation of8-(3-methylbutan-2-one-1-yl)-13-ethyl-2,3,9,10-tetraethoxydihydroprotoberberine (Compound No. 45)

15 G of 13-ethyl-2,3,9,10-tetraethoxyprotoberberine, 10 ml of water and60 ml of i-propyl methyl ketone were introduced into a 100 ml roundbottom flask, and 20 g of a 50% sodium hydroxide solution was addeddropwise to the mixture. The solution was stirred at room temperaturefor 10 minutes. The solvent was distilled off under reduced pressure toits half. The precipitate was filtered and recrystallized from methanolto give 6.78 g of the titled compound as a white crystal (m.p.: 103°C.).

¹H-NMR (300 MHz, DMSO-d₆) δ: 0.79(d, J=7.2 Hz, 3H), 0.86(d, J=6.9 Hz,3H), 1.33(m, 15H), 2.09(dd, 1H), 2.60(m, 6H), 4.00(m, 10H), 5.21(dd,1H), 6.81(s, 1H), 6.88(d, 1H), 6.91(d, 1H), 7.00(s, 1H)

EXAMPLE 46 Preparation of 13-ethyldihydropalmatine (Compound No. 46)

0.8 G of 13-ethylpalmatine and 0.83 g of potassium carbonate in a 50 mlround bottom flask were dissolved in 30 ml of methanol. After thesolution was cooled to 0° C. with ice, 0.05 g of sodium borohydride wasslowly added dropwise to it. The solution was allowed to stand for 1hour. The precipitate was filtered, and dissolved in ethyl acetate andthen the mixture was washed with water. The organic layer was dried overmagnesium sulfate, filtered and concentrated under reduced pressure toremove the solvent. The residue was recrystallized from methanol to give0.57 g of the titled compound as a yellow crystal (m.p.: 122° C.)

¹H-NMR (300 MHz, CDCl₃) δ: 1.34(t, J=7.5 Hz, 3H), 2.81(m, 4H), 3.08(m,2H), 3.85(s, 3H), 3.88(s, 3H), 3.91(s, 3H), 3.92(s, 3H), 4.27(s, 2H),6.68(s, 1H), 6.84(d, J=8.4 Hz, 1H), 7.03(d, J=8.4 Hz, 1H), 7.17(s, 1H)

EXAMPLE 47 Preparations3-ethyl-2,3,9,10-tetraethoxydihydroprotoberberine(Compound No. 47)

1.0 G of 13-ethyl-2,3,9,10-tetraethoxyprotoberberine and 0.83 g ofpotassium carbonate in a 50 ml round bottom flask were dissolved in 30ml of methanol. After the solution was cooled to 0° C. with ice, 0.05 gof sodium borohydride was slowly added dropwise to it. The solution wasallowed to stand for 1 hour. The solvent was distilled off under reducedpressure and the residue was extracted with dichloromethane. The organicphase was dried over magnesium sulfate, filtered and concentrated underreduced pressure to remove the solvent. The residue was recrystallizedfrom methanol to give 0.70 g of the titled compound as a yellow crystal(m.p.: 103° C.)

¹H-NMR (300 MHz, CDCl1₃) δ: 0.79(t, J=7.8 Hz, 3H), 1.38(m, 12H), 2.57(m,2H), 2.89(m, 1H), 3.13(m, 2H), 3.47(d, J=16.2 Hz, 1H), 3.68(m, 1H),4.13(m, 8H), 4.23(d, J=16.2 Hz, 1H), 6.63(s, 1H), 6.73(s, 1H), 6.78(d,J=8.4 Hz, 1H), 6.85(d, J=8.4 Hz, 1H)

EXAMPLE 48 Preparation of 8-methyl-13-ethyldihydropalmatine (CompoundNo. 48)

1.25 G of 13-ethylpalmatine in a 25 ml round bottom flask were dissolvedin 15 ml of tetrahydrofuran. After the solution was cooled to 0° C. withice, 1.5 ml of 3.0 M methylnagnesium chloride were slowly added using asyringe over 10 minutes. After stirring at 0° C. for 1.5 hours and atroom temperature for 30 minutes, the reaction mixture was quenched bypouring water. The solvent was distilled off under reduced pressure. Theresidue was dissolved into dichloromethane, washed with water. Theorganic phase was dried over magnesium sulfate, filtered andconcentrated under reduced pressure to remove the solvent. The residuewas recrystallized from ethyl acetate/n-hexane to give 0.93 g of thetitled compound as a yellow crystal (m.p.: 134° C.)

¹H-NMR (300 MHz, CDCl₃) δ: 1.10(d, J=6.3 Hz,3H), 1.33(t, J=7.5 Hz, 3H),2.75(m, 2H), 2.91(m, 2H), 3.26(m, 2H), 3.88(s, 3H), 3.91(s, 3H), 3.92(s,3H), 3.93(s, 3H), 4.75(q, J=6.3 Hz, 1H), 6.69(s, 1H), 6.82(d, J=8.7 Hz,1H), 7.04(d, J=8.7 Hz, 1H), 7.15(s, 1H)

EXAMPLE 49 Preparation of 8-ethyl-13-ethyldihydropalmatine (Compound No.49)

1.25 G of 13-ethylpalmatine in a 25 ml round bottom flask were dissolvedinto 15 ml of tetrahydrofuran. After the solution was cooled to 0° C.with ice, 6.0 ml of 1.0 M ethyl magnesium chloride were slowly addedusing a syringe over 10 minutes. After stirring at 0° C. for 1.5 hoursand at room temperature for 30 minutes, the reaction mixture wasquenched by pouring water. The solvent was distilled off under reducedpressure. The residue was dissolved into dichloromethane, washed withwater. The organic phase was dried over magnesium sulfate, filtered andconcentrated under reduced pressure to remove the solvent. The residuewas recrystallized from ethyl acetate/n-hexane to give 1.0 g of thetitled compound as a yellow crystal (m.p.: 153° C.)

¹H-NMR (300 MHz, CDCl₃) δ: 0.79(t, J=7.5 Hz, 3H), 1.30(t, J =7.5 Hz,3H), 1.61(m, 2H), 2.70(m, 2H), 2.90(m, 2H), 3.33(m, 2H), 3.88(s, 3H),3.90(s, 3H), 3.91(s, 3H), 3.93(s, 3H), 4.60(dd, 1H), 6.69(s, 1H),6.84(d, J=8.7 Hz, 1H), 7.03(d, J=8.7 Hz, 1H), 7.12(s, 1H)

EXAMPLE 50 Preparation of 8-n-butyl-13-ethyldihydropalmatine (CompoundNo. 50)

1.25 G of 13-ethylpalmatine in a 25 ml round bottom flask were dissolvedinto 15 ml of tetrahydrofuran. After the solution was cooled to 0° C.with ice, 3.0 ml of 1.6 M n-butylmagnesium chloride were slowly addedusing a syringe over 10 minutes. After stirring at 0° C. for 1.5 hoursand at room temperature for 30 minutes, the reaction mixture wasquenched by pouring water. The solvent was distilled off under reducedpressure. The residue was dissolved into dichloromethane, washed withwater. The organic phase was dried over magnesium sulfate, filtered andconcentrated under reduced pressure to remove the solvent. The residuewas recrystallized from ethyl acetate/n-hexane to give 1.3 g of thetitled compound as a yellow crystal (m.p.: 112° C.)

¹H-NMR (300 MHz, CDCl₃) δ: 0.78(t, J=6.9 Hz, 3H), 1.19(m, 4H), 1.28(t,J=7.2 Hz, 3H), 1.59(m, 2H), 2.70(m, 2H), 2.91(m, 2H), 3.34(m, 2H),3.88(s, 3H), 3.89(s, 3H), 3.91(s, 3H), 3.93(s, 3H), 4.61(dd, 1H),6.69(s, 1H), 6.84(d, J=8.4 Hz, 1H), 7.03(d, J=8.4 Hz, 1H), 7.12(s, 1H)

INDUSTRIAL APPLICABILITY

7,8,13,13α-tetradehydrocoridaline which is a pharmacological ingredientof Corydalis Turtschaninowii Besser and the compounds of formula (1) caneffectively inhibit sterol 14-reductase which is involved in the distalpathway of cholesterol biosynthesis, and thus, are especially effectivein treating hyper-cholesterolemia.

The compounds of formula (1) above have the activities to decrease totalcholesterol, LDL-cholesterol, and triglyceride levels and at the sametime, to decrease glucose level in an animal test. Therefore, they areeffective in diabetic hypercholesterolaemia and hyperlipidaemia.

Table 3 represents the relative activity for sterol 14-reductase of thecompound of formula (1) as set forth in Table 1. Among the compounds ofTable 1, Compound Nos. 5, 6, 8, 37, 38, 46 and 47 markedly inhibited thecholesterol biosynthesis in human HepG2 cell line compared with AY9944which is a comparative drug. In the animal test with Syrian GoldenHamster, Compound Nos. 5, 8, 37 and 46 have markedly decreased totalcholesterol, LDL-cholesterol, and triglyceride levels compared withlovastatin which is a commercially available comparativecholesterol-lowering agent.

TABLE 3 Relative In Vitro activity of the compound of formula (1) EnzymeCompound Compound No. Activity No. Enzyme Activity 1 ++ 26 + 2 ++ 27 +3 + 28 + 4 ++ 29 + 5 +++ 30 + 6 +++ 31 + 7 ++ 32 + 8 +++ 33 + 9 + 34 +10 + 35 + 11 ++ 36 + 12 ++ 37 +++ 13 + 38 +++ 14 + 39 ++ 15 + 40 ++ 16++ 41 + 17 ++ 42 + 18 + 43 + 19 + 44 ++ 20 + 45 ++ 21 + 46 +++ 22 + 47+++ 23 + 48 + 24 + 49 + 25 ++ 50 + +: 100 μM or more of IC₅₀ value ++:10-100 μM of IC₅₀ value +++: 1 μM or below of IC₅₀ value

TABLE 4 Total HDL LDL cholesterol cholesterol cholesterol Trigly-cerideGlucose Group No. n (mg/dl) (mg/dl) (mg/dl) (mg/dl) (mg/dl) normal diet5 126.6 ± 2.0  52.8 ± 4.2 42.2 ± 2.5 132.4 ± 25.3 182.2 ± 24.6 controlnormal diet + 5 97.4 ± 3.4 51.4 ± 2.6 29.9 ± 1.9 182.6 ± 17.0 184.6 ±23.2 lovastatin (−22.7%) (−2.6%) (−29.1%) (−37.8%) (+1.0%) 6.0 mg/kg/daynormal diet + 5 94.0 ± 6.6 47.5 ± 3.0 24.5 ± 1.8 90.4 ± 8.9 162.2 ± 11.3comp. 8 (−25.4%) (−1.8%) (−42.0%) (−31.7%) (−10.9%) 6.0 mg/kg/day normaldiet + 5 97.0 ± 5.6 51.1 ± 3.0 24.9 ± 3.0  94.7 ± 11.5 160.2 ± 20.9Comp. 5 (−23.5%) (−3.2%) (−41.2%) (−28.5%) (−12.4%) 6.0 mg/kg/day normaldiet + 5 83.8 ± 5.6 54.2 ± 3.0 20.2 ± 2.0  68.8 ± 11.5 140.4 ± 15  Comp. 37 (−33.5%) (+2.0%) (−52.1%) (−48.1%) (−23.0%) 6.0 mg/kg/daynormal diet + 5 82.4 ± 5.4 49.2 ± 2.9 20.8 ± 2.3  85.2 ± 11.0 158.8 ±16   Comp. 46 (−34.6%) (−6.8%) (−50.7%) (−35.6%) (−12.7%) 6.0 mg/kg/day

Meanwhile, the toxicity of the compounds of the present invention wasinvestigated as follows: i.e., the compounds were suspended intopropylene glycol and then orally administered into each of 5 male andfemale SD rats at the age of 5-weeks that were fasted for 12 hours.Under the usual breeding conditions, general symptoms, weight change andlethal case of the above rats were monitored for two weeks. At the doseover 2,000 mg/kg of the compound nos. 5, 37, and 46, general symptomsand the body weight change of the animals were normal and the lethalcase was not observed. Rats were safe against the dose of 700 mg/kg ofcompound no.8. The toxicity data for the representative compounds(Compound No.5, 8, 37 and 46) is set forth in Table 5.

TABLE 5 Acute Toxicity (mg/kg) administration Comp. No. animal route sexLD₅₀ Comp. 5 rats oral male >5,000 female >5,000 Comp. 8 rats oralmale >925 female >760 Comp. 37 rats oral male >2,500 female >2,000 Comp.46 rats oral male >3,000 female >3,000

As evident from the above descriptions, the compound of formula (1)inhibits sterol 14-reductase which is an enzyme in the distal stage ofthe cholesterol biosynthesis, thereby being effective in treatment ofhypercholesterolemia and hyperlipidaemia and safe in an aspect oftoxicity.

What is claimed is:
 1. A compound of formula (1b) or a pharmaceuticallyacceptable salt thereof;

wherein R¹ and R² which may be the same or different from each other,represent a hydroxy group or an alkoxy group having 1 to 4 carbon atomsor both R¹ and R² represent a methylenedioxy group; R³ represents analkyl group having 1 to 8 carbon atoms, a ketonyl group having 3 to 7carbon atoms, a branched ketonyl group, a cycloalkyl group having 3 to 7carbon atoms, a cyanomethyl group, a 2-cyclopentanonyl group, or a2-cyclohexanonyl group; R⁴ and R⁵ which may be the same or differentfrom each other, represent a hydroxy group, a hydroxyethylamino group oran alkoxy group having 1to 4 carbon atoms; R⁶ represents a hydrogenatom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having3 to 8 carbon atoms, or a cycloalkylalkyl group having 3 to 7 carbonatoms.
 2. The compound of formula (1b) or a pharmaceutically acceptablesalt thereof according to claim 1, wherein R¹, R², R⁴ and R⁵ eachrepresents methoxy, R³ represents 2-oxopropyl, and R⁶ represents ethyl.3. The compound of formula (1b) or a pharmaceutically acceptable saltthereof according to claim 1, wherein R¹, R², R⁴ and R⁵ each representsmethoxy, R³ represents a hydrogen atom, and R⁶ represents ethyl.
 4. Aprocess for preparing a compound of formula (1 b) or a pharmaceuticallyacceptable salt thereof, which comprises: (a) reacting a berberinederivative of formula (5a) with an alkyl halide, a salt of sulfuric acidor a salt of nitric acid in a polar solvent or a non-polar solvent toproduce 13-alkylberberine halide of formula (6a); (b) reacting the13-alkylberberine halide of formula (6a) with a Lewis acid to obtain anintermediate product and then subjecting the intermediate product to ahydrolysis reaction with a dilute acid to produce a compound of formula(7a); (c) methylating the compound of formula (7a) with a methylatingagent to produce a compound of formula (1); (d) transforming thecompound of formula (1) into a salt thereof; and (e) reducing aquaternary ammonium salt of the compound of formulae (6a), (7a), or (1)with sodium borohydride (NaBH₄) in the presence of potassium carbonateto produce a tertiary amine compound of formula (1b)

wherein R¹ and R² which may be the same or different from each other,represent a hydroxy group or an alkoxy group having 1 to 4 carbon atomsor both R¹ and R² represent a methylenedioxy group; R³ represents analkyl group having 1 to 8 carbon atoms, a cyclic ketonyl group having 3to 7 carbon atoms, a branched ketonyl group. a cycloalkyl group having 3to 7 carbon atoms, a cyanomethyl group, a 2-cyclopentanonyl group, or a2-cyclohexanonyl group; R⁴ and R⁵ which may be the same or differentfrom each other, represent a hydroxy group, a hydroxyethylamino group oran alkoxy group having 1 to 4 carbon atoms; R⁶ represents a hydrogenatom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having3 to 8 carbon atoms, or a cycloalkylalkyl group having 3 to 7 carbonatoms; X represents a halide, a sulfate, or a nitrate; and Z representsa halide.
 5. The process according to claim 4, wherein the solvent inthe step (a) is selected from the group consisting of acetonitrile andtoluene.
 6. The process according to claim 4, wherein the salt in thestep (e) is selected from the group consisting of halide, sulfate,nitrate, acetate, cinnamate, tinate, maleate, succinate, citrate,fumarate and fatty acid salt.
 7. A method for treating hyperlipidaemiawhich comprises administering into a patient in need thereof apharmaceutically acceptable amount of a compound of formula (1b) or apharmaceutically acceptable salt thereof;

wherein R¹ and R² which may be the same or different from each other,represent a hydroxy group or an alkoxy group having 1 to 4 carbon atomsor both R¹ and R² represent a methylenedioxy group; R³ represents ahydrogen atom, an alkyl group having 1 to 8 carbon atoms, a ketonylgroup having 3 to 7 carbon atoms, a cycloalkyl group having 3 to 7carbon atoms, a cyanomethyl group, a 2-cyclopentanonyl group, or a2-cyclohexanonyl group; R⁴ and R⁵ which may be the same or differentfrom each other, represent a hydroxy group, a hydroxyethylamino group oran alkoxy group having 1 to 4 carbon atoms; R⁶ represents a hydrogenatom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having3 to 8 carbon atoms, or a cycloalkylalkyl group having 3 to 7 carbonatoms, and a pharmaceutically acceptable excipient.
 8. A methodaccording to claim 7, wherein R¹, R², R⁴ and R⁵ each represents methoxy,R³ represents 2-oxopropyl, and R⁶ represents ethyl.
 9. A methodaccording to claim 7, wherein R¹, R², R⁴ and R⁵ each represents methoxy,R³ represents a hydrogen atom, and R⁶ represents ethyl.